Circadian (daily) rhythms are a crucial component of human health, especially of mental health. The "clocks" underlying these rhythms regulate sleep, alertness, hormones, metabolic activities of various tissues, and many other biological processes. Appropriate daily regulation of these processes to attain optimal phase relationships is crucial for mental health. We have discovered significant associations of polymorphisms in two circadian clock genes with sleep and drug/alcohol abuse phenotypes in humans suffering from unipolar Major Depressive Disorder (MDD). Clock gene polymorphisms can cause atypical phasing of the human circadian system (or of other metabolic pathways) leading to sleep disorders and/or metabolic disorders. The central hypothesis of this proposal is that depression pushes the susceptibilities for hypersomnia and substance abuse closer to a "phenotype threshold," and that the polymorphisms we have identified in these two clock genes modulate the activities of these genes so as to enhance those susceptibilities such that the hypersomnia/substance abuse phenotypes are expressed. We will test that hypothesis by analyzing clock gene polymorphisms in a larger sample of depressed subjects and compare those patterns with data from a characterized control population of non-depressed subjects. In addition, initial studies towards understanding the functional cell/molecular basis for these genetic polymorphisms will be conducted using state-of-the art luminescence assays of clock gene function in mammalian cells. This project is appropriate for the NIH Exploratory/Developmental Research Grant Program because it proposes to develop an novel research area-namely the interface between circadian clocks, depression, and genetics-that will facilitate the prediction, diagnosis, and treatment of phenotypes related to depression. PUBLIC HEALTH RELEVANCE: This project will use genetic techniques to study the relationship between daily biological clocks and depression in humans. In particular, hypersomnia and drug/alcohol abuse are correlated with biological clock genes in depressed humans. This investigation could lead to new genetic methods of diagnosis and/or treatment of sleep disorders and substance abuse in depressed humans.